title: Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity.
abstract: The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl(-) channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whether the inhibition of CFTR could protect against cisplatin-induced nephrotoxicity. Using a renal proximal cell line, we show that the specific inhibitor of CFTR, CFTR(inh)-172, prevents cisplatin-induced cell death and apoptosis by modulating the intracellular reactive oxygen species balance and the intracellular GSH concentration. This CFTR(inh)-172-mediated protective effect occurs without affecting cellular cisplatin uptake or the formation of platinum-DNA adducts. The protective effect of CFTR(inh)-172 in cisplatin-induced nephrotoxicity was also investigated in a rat model. Five days after receiving a single cisplatin injection (5 mg/kg), rats exhibited renal failure, as evidenced by the alteration of biochemical and functional parameters. Pretreatment of rats with CFTR(inh)-172 (1 mg/kg) prior to cisplatin injection significantly prevented these deleterious cisplatin-induced nephrotoxic effects. Finally, we demonstrate that CFTR(inh)-172 does not impair cisplatin-induced cell death in the cisplatin-sensitive A549 cancer cell line. In conclusion, the use of a specific inhibitor of CFTR may represent a novel therapeutic approach in the prevention of nephrotoxic side effects during cisplatin treatment without affecting its antitumor efficacy.
authors.affiliation: University of Nice-Sophia Antipolis, LP2M CNRS-3472, Laboratories of Excellence, Ion Channel Science and Therapeutics, Parc Valrose, Nice 06108, France.
authors.forename: I
authors.initials: I
authors.lastname: Rubera
authors.forename: C
authors.initials: C
authors.lastname: Duranton
authors.forename: N
authors.initials: N
authors.lastname: Melis
authors.forename: M
authors.initials: M
authors.lastname: Cougnon
authors.forename: B
authors.initials: B
authors.lastname: Mograbi
authors.forename: M
authors.initials: M
authors.lastname: Tauc
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D010984:Platinum / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001565:Benzoates; D015415:Biomarkers; D018736:DNA Adducts; D017382:Reactive Oxygen Species; D053778:Thiazolidines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D010984:Platinum; D053148:Caspase 3; D005978:Glutathione; D002945:Cisplatin